Histamine in Neurotransmission and Brain Diseases

  • Saara Nuutinen
  • Pertti PanulaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 709)


Apart from its central role in the mediation of allergic reactions, gastric acid secretion and inflammation in the periphery, histamine serves an important function as a neurotransmitter in the central nervous system. The histaminergic neurons originate from the tuberomamillary nucleus of the posterior hypothalamus and send projections to most parts of the brain. The central histamine system is involved in many brain functions such as arousal, control of pituitary hormone secretion, suppression of eating and cognitive functions. The effects of neuronal histamine are mediated via G-protein-coupled H1-H4 receptors. The prominent role of histamine as a wake-promoting substance has drawn interest to treat sleep-wake disorders, especially narcolepsy, via modulation of H3 receptor function. Post mortem studies have revealed alterations in histaminergic system in neurological and psychiatric diseases. Brain histamine levels are decreased in Alzheimer’s disease patients whereas abnormally high histamine concentrations are found in the brains of Parkinson’s disease and schizophrenic patients. Low histamine levels are associated with convulsions and seizures. The release of histamine is altered in response to different types of brain injury: e.g. increased release of histamine in an ischemic brain trauma might have a role in the recovery from neuronal damage. Neuronal histamine is also involved in the pain perception. Drugs that increase brain and spinal histamine concentrations have antinociceptive properties. Histaminergic drugs, most importantly histamine H3 receptors ligands, have shown efficacy in many animal models of the above-mentioned disorders. Ongoing clinical trials will reveal the efficacy and safety of these drugs in the treatment of human patients.


Histaminergic Neuron Histaminergic System Histamine Synthesis Brain Histamine Neuronal Histamine 
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  1. 1.
    Abel JJ, Kubota S. On the presence of histamine (-iminazolylethylamine) in the hypophysis cerebri and other tissues of the body and its occurence among the hydrolytic decomposition products of proteins. J Pharmacol Exp Ther 1919; 13:243–300.Google Scholar
  2. 2.
    Garbarg M, Barbin G, Bischoff S et al. Evidence for a specific decarboxylase involved in histamine synthesis in an ascending pathway in rat brain. Agents Actions 1974; 4:181.PubMedGoogle Scholar
  3. 3.
    Watanabe T et al. Evidence for the presence of a histaminergic neuron system in the rat brain: an immunohistochemical analysis. Neurosci Lett 1983; 39:249–254.PubMedGoogle Scholar
  4. 4.
    Panula P, Yang HY, Costa E. Histamine-containing neurons in the rat hypothalamus. Proc Natl Acad Sci. USA 1984; 81:2572–2576.PubMedGoogle Scholar
  5. 5.
    Haas H, Panula P. The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci 2003; 4:121–130.PubMedGoogle Scholar
  6. 6.
    Ericson H, Watanabe T, Kohler C. Morphological analysis of the tuberomammillary nucleus in the rat brain: delineation of subgroups with antibody against l-histidine decarboxylase as a marker. J Comp Neurol 1987; 263:1–24.PubMedGoogle Scholar
  7. 7.
    Panula P, Airaksinen MS, Pirvola U et al. A histamine-containing neuronal system in human brain. Neuroscience 1990; 34:127–132.PubMedGoogle Scholar
  8. 8.
    Martres MP, Baudry M, Schwartz JC. Histamine synthesis in the developing rat brain: evidence for a multiple compartmentation. Brain Res 1975; 83:261–275.PubMedGoogle Scholar
  9. 9.
    Katoh Y et al. Histamine production by cultured microglial cells of the mouse. Neurosci Lett 2001; 305:181–184.PubMedGoogle Scholar
  10. 10.
    Karlstedt K, Nissinen M, Michelsen KA et al. Multiple sites of l-histidine decarboxylase expression in mouse suggest novel developmental functions for histamine. Dev Dyn 2001; 221:81–91.PubMedGoogle Scholar
  11. 11.
    Molina-Hernandez A, Velasco I. Histamine induces neural stem cell proliferation and neuronal differentiation by activation of distinct histamine receptors. J Neurochem 2008; 106:706–717.PubMedGoogle Scholar
  12. 12.
    Kukko-Lukjanov TK, Panula P. Subcellular distribution of histamine, GABA and galanin in tuberomamillary neurons in vitro. J Chem Neuroanat 2003; 25:279–292.PubMedGoogle Scholar
  13. 13.
    Erickson JD, Schafer MK, Bonner TI et al. Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter. Proc Natl Acad Sci USA 1996; 93:5166–5171.PubMedGoogle Scholar
  14. 14.
    Merickel A, Edwards RH. Transport of histamine by vesicular monoamine transporter-2. Neuropharmacology 1995; 34:1543–1547.PubMedGoogle Scholar
  15. 15.
    Reilly MA, Schayer RW. In vivo studies on histamine catabolism and its inhibition. Br J Pharmacol 1970; 38:478–489.PubMedGoogle Scholar
  16. 16.
    Hough LB, Domino EF. Tele-methylhistamine oxidation by type B monoamine oxidase. J Pharmacol Exp Ther 1979; 208:422–428.PubMedGoogle Scholar
  17. 17.
    Prell GD, Morrishow AM, Duoyon E et al. Inhibitors of histamine methylation in brain promote formation of imidazoleacetic acid, which interacts with GABA receptors. J Neurochem 1997; 68:142–151.PubMedGoogle Scholar
  18. 18.
    Arrang JM, Garbarg M, Schwartz JC. Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature 1983; 302:832–837.PubMedGoogle Scholar
  19. 19.
    Schlicker E, Malinowska B, Kathmann M et al. Modulation of neurotransmitter release via histamine H3 heteroreceptors. Fundam Clin Pharmacol 1994; 8:128–137.PubMedGoogle Scholar
  20. 20.
    Brown RE, Stevens DR, Haas HL. The physiology of brain histamine. Prog Neurobiol 2001; 63:637–672.PubMedGoogle Scholar
  21. 21.
    Ferrada C et al. Interactions between histamine H3 and dopamine D2 receptors and the implications for striatal function. Neuropharmacology 2008; 55:190–197.PubMedGoogle Scholar
  22. 22.
    Morisset S et al. High constitutive activity of native H3 receptors regulates histamine neurons in brain. Nature 2000; 408:860–864.PubMedGoogle Scholar
  23. 23.
    Sander K, Kottke T, Stark H. Histamine H3 receptor antagonists go to clinics. Biol Pharm Bull 2008; 31:2163–2181.PubMedGoogle Scholar
  24. 24.
    Arrang JM, Morisset S, Gbahou F. Constitutive activity of the histamine H3 receptor. Trends Pharmacol Sci 2007; 28:350–357.PubMedGoogle Scholar
  25. 25.
    Drutel G et al. Identification of rat H3 receptor isoforms with different brain expression and signaling properties. Mol Pharmacol 2001; 59:1–8.PubMedGoogle Scholar
  26. 26.
    Rouleau A et al. Cloning and expression of the mouse histamine H3 receptor: evidence for multiple isoforms. J Neurochem 2004; 90:1331–1338.PubMedGoogle Scholar
  27. 27.
    Lovenberg TW et al. Cloning and functional expression of the human histamine H3 receptor. Mol Pharmacol 1999; 55:1101–1107.PubMedGoogle Scholar
  28. 28.
    Strakhova MI et al. Localization of histamine H(4) receptors in the central nervous system of human and rat. Brain Res 2008.Google Scholar
  29. 29.
    Sherin JE, Shiromani PJ, McCarley RW et al. Activation of ventrolateral preoptic neurons during sleep. Science 1996; 271:216–219.PubMedGoogle Scholar
  30. 30.
    Lin JS, Hou Y, Sakai K et al. Histaminergic descending inputs to the mesopontine tegmentum and their role in the control of cortical activation and wakefulness in the cat. J Neurosci 1996; 16:1523–1537.PubMedGoogle Scholar
  31. 31.
    Lin JS. Brain structures and mechanisms involved in the control of cortical activation and wakefulness, with emphasis on the posterior hypothalamus and histaminergic neurons. Sleep Med Rev 2000; 4:471–503.PubMedGoogle Scholar
  32. 32.
    Lin JS et al. Involvement of histaminergic neurons in arousal mechanisms demonstrated with H3-receptor ligands in the cat. Brain Res 1990; 523:325–330.PubMedGoogle Scholar
  33. 33.
    Kiyono S et al. Effects of alpha-fluoromethylhistidine on sleep-waking parameters in rats. Physiol Behav 1985; 34:615–617.PubMedGoogle Scholar
  34. 34.
    Parmentier R et al. Anatomical, physiological and pharmacological characteristics of histidine decarboxylase knock-out mice: evidence for the role of brain histamine in behavioral and sleep-wake control. J Neurosci 2002; 22:7695–7711.PubMedGoogle Scholar
  35. 35.
    Knigge U, Warberg J. The role of histamine in the neuroendocrine regulation of pituitary hormone secretion. Acta Endocrinol (Copenh) 1991; 124:609–619.Google Scholar
  36. 36.
    Armstrong WE, Sladek CD. Evidence for excitatory actions of histamine on supraoptic neurons in vitro: mediation by an H1-type receptor. Neuroscience 1985; 16:307–322.PubMedGoogle Scholar
  37. 37.
    Haas HL, Wolf P, Nussbaumer JC. Histamine: action on supraoptic and other hypothalamic neurones of the cat. Brain Res 1975; 88:166–170.PubMedGoogle Scholar
  38. 38.
    Bhargava KP, Kulshrestha VK, Santhakumari G et al. Mechanism of histamine-induced antidiuretic response. Br J Pharmacol 1973; 47:700–706.PubMedGoogle Scholar
  39. 39.
    Tuomisto L, Eriksson L, Fyhrquist F. Vasopressin release by histamine in the conscious goat. Eur J Pharmacol 1980; 63:15–24.PubMedGoogle Scholar
  40. 40.
    Libertun C, McCann SM. The possible role of histamine in the control of prolactin and gonadotropin release. Neuroendocrinology 1976; 20:110–120.PubMedGoogle Scholar
  41. 41.
    Hashimoto H, Noto T, Nakajima T. A study on the release mechanism of vasopressin and oxytocin. Neuropeptides 1988; 12:199–206.PubMedGoogle Scholar
  42. 42.
    Miklos IH, Kovacs KJ. Functional heterogeneity of the responses of histaminergic neuron subpopulations to various stress challenges. Eur J Neurosci 2003; 18:3069–3079.PubMedGoogle Scholar
  43. 43.
    Kalucy RS. Drug-induced weight gain. Drugs 1980; 19:268–278.PubMedGoogle Scholar
  44. 44.
    Jorgensen EA, Knigge U, Warberg J et al. Histamine and the regulation of body weight. Neuroendocrinology 2007; 86:210–214.PubMedGoogle Scholar
  45. 45.
    Morimoto T et al. Involvement of the histaminergic system in leptin-induced suppression of food intake. Physiol Behav 1999; 67:679–683.PubMedGoogle Scholar
  46. 46.
    Masaki T, Yoshimatsu H, Chiba S et al. Targeted disruption of histamine H1-receptor attenuates regulatory effects of leptin on feeding, adiposity and UCP family in mice. Diabetes 2001; 50:385–391.PubMedGoogle Scholar
  47. 47.
    Masaki T et al. Involvement of hypothalamic histamine H1 receptor in the regulation of feeding rhythm and obesity. Diabetes 2004; 53:2250–2260.PubMedGoogle Scholar
  48. 48.
    Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev 2008; 88:1183–1241.PubMedGoogle Scholar
  49. 49.
    Bugajski J, Janusz Z. Lipolytic responses induced by intracerebroventricular administration of histamine in the rat. Agents Actions 1981; 11:147–150.PubMedGoogle Scholar
  50. 50.
    Yoshimatsu H et al. Histidine induces lipolysis through sympathetic nerve in white adipose tissue. Eur J Clin Invest 2002; 32:236–241.PubMedGoogle Scholar
  51. 51.
    Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet 2007; 369:499–511.PubMedGoogle Scholar
  52. 52.
    John J, Wu MF, Boehmer LN et al. Cataplexy-active neurons in the hypothalamus: implications for the role of histamine in sleep and waking behavior. Neuron 2004; 42:619–634.PubMedGoogle Scholar
  53. 53.
    Scharf M et al. Efficacy and Safety of Doxepin 1 mg, 3 mg and 6 mg in Elderly Patients With Primary Insomnia: a Randomized, Double-Blind, Placebo-Controlled Crossover Study. J Clin Psychiatry 2008.Google Scholar
  54. 54.
    Panula P et al. Neuronal histamine déficit in Alzheimer’s disease. Neuroscience 1998; 82:993–997.PubMedGoogle Scholar
  55. 55.
    Mazurkiewicz-Kwilecki IM, Nsonwah S. Changes in the regional brain histamine and histidine levels in postmortem brains of Alzheimer patients. Can J Physiol Pharmacol 1989; 67:75–78.PubMedGoogle Scholar
  56. 56.
    Nakamura S et al. Loss of large neurons and occurrence of neurofibrillary tangles in the tuberomammillary nucleus of patients with Alzheimer’s disease. Neurosci Lett 1993; 151:196–199.PubMedGoogle Scholar
  57. 57.
    Airaksinen MS, Reinikainen K, Riekkinen P et al. Neurofibrillary tangles and histamine-containing neurons in Alzheimer hypothalamus. Agents Actions 1991; 33:104–107.PubMedGoogle Scholar
  58. 58.
    Higuchi M et al. Histamine H(1) receptors in patients with Alzheimer’s disease assessed by positron emission tomography. Neuroscience 2000; 99:721–729.PubMedGoogle Scholar
  59. 59.
    Medhurst AD et al. GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer’s disease brain and improves cognitive performance in preclinical models. J Pharmacol Exp Ther 2007; 321:1032–1045.PubMedGoogle Scholar
  60. 60.
    Xu C et al. Histamine innervation and activation of septohippocampal GABAergic neurones: involvement of local ACh release. J Physiol 2004; 561:657–670.PubMedGoogle Scholar
  61. 61.
    Jin C, Lintunen M, Panula P. Histamine H(1) and H(3) receptors in the rat thalamus and their modulation after systemic kainic acid administration. Exp Neurol 2005; 194:43–56.PubMedGoogle Scholar
  62. 62.
    Jin CY, Panula P. The laminar histamine receptor system in human prefrontal cortex suggests multiple levels of histaminergic regulation. Neuroscience 2005; 132:137–149.PubMedGoogle Scholar
  63. 63.
    Ligneau X et al. BF2.649 (1-{3-(3-(4-Chlorophenyl)propoxy)propyl}piperidine, hydrochloride), a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: preclinical pharmacology. J Pharmacol Exp Ther 2007; 320:365–375.PubMedGoogle Scholar
  64. 64.
    Fox GB et al. Pharmacological properties of ABT-239 (4-(2-{2-((2R)-2-Methylpyrrolidinyl)ethyl}-benzofuran-5-yl)benzonitrile): II. Neurophysiological characterization and broad preclinical efficacy in cognition and schizophrenia of a potent and selective histamine H3 receptor antagonist. J Pharmacol Exp Ther 2005; 313:176–190.PubMedGoogle Scholar
  65. 65.
    Cowart M et al. 4-(2-(2-(2(R)-methylpyrrolidin-l-yl)ethyl)benzofuran-5-yl)benzonitrile and related 2-aminoethylbenzofuran H3 receptor antagonists potently enhance cognition and attention. J Med Chem 2005; 48:38–55.PubMedGoogle Scholar
  66. 66.
    Prell GD et al. Histamine metabolites in cerebrospinal fluid of patients with chronic schizophrenia: their relationships to levels of other aminergic transmitters and ratings of symptoms. Schizophr Res 1995; 14:93–104.PubMedGoogle Scholar
  67. 67.
    Nakai T et al. Decreased histamine H1 receptors in the frontal cortex of brains from patients with chronic schizophrenia. Biol Psychiatry 1991; 30:349–356.PubMedGoogle Scholar
  68. 68.
    Iwabuchi K et al. Histamine H1 receptors in schizophrenic patients measured by positron emission tomography. Eur Neuropsychopharmacol 2005; 15:185–191.PubMedGoogle Scholar
  69. 69.
    Morisset S et al. Acute and chronic effects of methamphetamine on tele-methylhistamine levels in mouse brain: selective involvement of the D(2) and not D(3) receptor. J Pharmacol Exp Ther 2002; 300:621–628.PubMedGoogle Scholar
  70. 70.
    Itoh Y, Oishi R, Nishibori M et al. Phencyclidine and the dynamics of mouse brain histamine. J Pharmacol Exp Ther 1985; 235:788–792.PubMedGoogle Scholar
  71. 71.
    Jin C, Anichtchik O, Panula P. Altered histamine H3 receptor radioligand binding in postmortem brain samples from subjects with psychiatric diseases. Br J Pharmacol, In press 2009.Google Scholar
  72. 72.
    Jin CY, Kalimo H, Panula P. The histaminergic system in human thalamus: correlation of innervation to receptor expression. Eur J Neurosci 2002; 15:1125–1138.PubMedGoogle Scholar
  73. 73.
    Browman KE et al. Enhancement of prepulse inhibition of startle in mice by the H3 receptor antagonists thioperamide and ciproxifan. Behav Brain Res 2004; 153:69–76.PubMedGoogle Scholar
  74. 74.
    Esbenshade TA et al. The histamine H3 receptor: an attractive target for the treatment of cognitive disorders. BrJ Pharmacol 2008; 154:1166–1181.Google Scholar
  75. 75.
    Kaminsky R, Moriarty TM, Bodine J et al. Effect of famotidine on deficit symptoms of schizophrenia. Lancet 1990; 335:1351–1352.PubMedGoogle Scholar
  76. 76.
    Martinez MC. Famotidine in the management of schizophrenia. Ann Pharmacother 1999; 33:742–747.PubMedGoogle Scholar
  77. 77.
    Anichtchik OV, Rinne JO, Kalimo H et al. An altered histaminergic innervation of the substantia nigra in Parkinson’s disease. Exp Neurol 2000; 163:20–30.PubMedGoogle Scholar
  78. 78.
    Rinne JO et al. Increased brain histamine levels in Parkinson’s disease but not in multiple system atrophy. J Neurochem 2002; 81:954–960.PubMedGoogle Scholar
  79. 79.
    Agundez JA et al. Nonsynonymous polymorphisms of histamine-metabolising enzymes in patients with Parkinson’s disease. Neuromolecular Med 2008; 10:10–16.PubMedGoogle Scholar
  80. 80.
    Anichtchik OV, Peitsaro N, Rinne JO et al. Distribution and modulation of histamine H(3) receptors in basal ganglia and frontal cortex of healthy controls and patients with Parkinson’s disease. Neurobiol Dis 2001; 8:707–716.PubMedGoogle Scholar
  81. 81.
    Goodchild RE et al. Distribution of histamine H3-receptor binding in the normal human basal ganglia: comparison with Huntington’s and Parkinson’s disease cases. Eur J Neurosci 1999; 11:449–456.PubMedGoogle Scholar
  82. 82.
    Ryu JH, Yanai K, Watanabe T. Marked increase in histamine H3 receptors in the striatum and substantia nigra after 6-hydroxydopamine-induced denervation of dopaminergic neurons: an autoradiographic study. Neurosci Lett 1994; 178:19–22.PubMedGoogle Scholar
  83. 83.
    Anichtchik OV et al. Modulation of histamine H3 receptors in the brain of 6-hydroxydopamine-lesioned rats. Eur J Neurosci 2000; 12:3823–3832.PubMedGoogle Scholar
  84. 84.
    Garcia M, Floran B, Arias-Montano JA et al. Histamine H3 receptor activation selectively inhibits dopamine D1 receptor-dependent (3H)GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata. Neuroscience 1997; 80:241–249.PubMedGoogle Scholar
  85. 85.
    Threlfell S et al. Histamine H3 receptors inhibit serotonin release in substantia nigra pars reticulata. J Neurosci 2004; 24:8704–8710.PubMedGoogle Scholar
  86. 86.
    Nowak P et al. Histamine H(3) receptor ligands modulate L-dopa-evoked behavioral responses and l-dopa derived extracellular dopamine in dopamine-denervated rat striatum. Neurotox Res 2008; 13:231–240.PubMedGoogle Scholar
  87. 87.
    Gomez-Ramirez J, Johnston TH, Visanji NP et al. Histamine H3 receptor agonists reduce l-dopa-induced chorea, but not dystonia, in the MPTP-lesioned nonhuman primate model of Parkinson’s disease. Mov Disord 2006; 21:839–846.PubMedGoogle Scholar
  88. 88.
    McGeer PL, Itagaki S, Boyes BE et al. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 1988; 38:1285–1291.PubMedGoogle Scholar
  89. 89.
    Whitton PS. Inflammation as a causative factor in the aetiology of Parkinson’s disease. Br J Pharmacol 2007; 150:963–976.PubMedGoogle Scholar
  90. 90.
    Carvey PM et al. 6-Hydroxydopamine-induced alterations in blood-brain barrier permeability. Eur J Neurosci 2005; 22:1158–1168.PubMedGoogle Scholar
  91. 91.
    Faucheux BA, Bonnet AM, Agid Y et al. Blood vessels change in the mesencephalon of patients with Parkinson’s disease. Lancet 1999; 353:981–982.PubMedGoogle Scholar
  92. 92.
    Kortekaas R et al. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol 2005; 57:176–179.PubMedGoogle Scholar
  93. 93.
    Fogel WA et al. Neuronal storage of histamine in the brain and tele-methylimidazoleacetic acid excretion in portocaval shunted rats. J Neurochem 2002; 80:375–382.PubMedGoogle Scholar
  94. 94.
    Haruyama W et al. The relationship between drug treatment and the clinical characteristics of febrile seizures. World J Pediatr 2008; 4:202–205.PubMedGoogle Scholar
  95. 95.
    Yokoyama H et al. Histamine levels and clonic convulsions of electrically-induced seizure in mice: the effects of alpha-fluoromethylhistidine and metoprine. Naunyn Schmiedebergs Arch Pharmacol 1992; 346:40–45.PubMedGoogle Scholar
  96. 96.
    Chen Z, Li WD, Zhu LJ et al. Effects of histidine, a precursor of histamine, on pentylenetetrazole-induced seizures in rats. Acta Pharmacol Sin 2002; 23:361–366.PubMedGoogle Scholar
  97. 97.
    Fujii Y, Tanaka T, Harada C et al. Epileptogenic activity induced by histamine H(1) antagonists in amygdala-kindled rats. Brain Res 2003; 991:258–261.PubMedGoogle Scholar
  98. 98.
    Yokoyama H, Sato M, Iinuma K et al. Centrally acting histamine H1 antagonists promote the development of amygdala kindling in rats. Neurosci Lett 1996; 217:194–196.PubMedGoogle Scholar
  99. 99.
    Hirai T et al. Development of amygdaloid kindling in histidine decarboxylase-deficient and histamine H1 receptor-deficient mice. Epilepsia 2004; 45:309–313.PubMedGoogle Scholar
  100. 100.
    Kiviranta T, Tuomisto L, Airaksinen EM. Histamine in cerebrospinal fluid of children with febrile convulsions. Epilepsia 1995; 36:276–280.PubMedGoogle Scholar
  101. 101.
    Onodera K, Tuomisto L, Tacke U et al. Strain differences in regional brain histamine levels between genetically epilepsy-prone and resistant rats. Methods Find Exp Clin Pharmacol 1992; 14:13–16.PubMedGoogle Scholar
  102. 102.
    Kukko-Lukjanov TK et al. Histaminergic neurons protect the developing hippocampus from kainic acid-induced neuronal damage in an organotypic coculture system. J Neurosci 2006; 26:1088–1097.PubMedGoogle Scholar
  103. 103.
    Dai H et al. Histamine protects against NMDA-induced necrosis in cultured cortical neurons through H receptor/cyclic AMP/protein kinase A and H receptor/GABA release pathways. J Neurochem 2006; 96:1390–1400.PubMedGoogle Scholar
  104. 104.
    Yokoyama H, Onodera K, Iinuma K et al. Effect of thioperamide, a histamine H3 receptor antagonist, on electrically induced convulsions in mice. Eur J Pharmacol 1993; 234:129–133.PubMedGoogle Scholar
  105. 105.
    Yokoyama H et al. Clobenpropit (VUF-9153), a new histamine H3 receptor antagonist, inhibits electrically induced convulsions in mice. Eur J Pharmacol 1994; 260:23–28.PubMedGoogle Scholar
  106. 106.
    Harada C et al. Intracerebroventricular administration of histamine H3 receptor antagonists decreases seizures in rat models of epilepsia. Methods Find Exp Clin Pharmacol 2004; 26:263–270.PubMedGoogle Scholar
  107. 107.
    Vohora D, Pal SN, Pillai KK. Histamine and selective H3-receptor ligands: a possible role in the mechanism and management of epilepsy. Pharmacol Biochem Behav 2001; 68:735–741.PubMedGoogle Scholar
  108. 108.
    Dux E et al. The blood-brain barrier in hypoxia: ultrastructural aspects and adenylate cyclase activity of brain capillaries. Neuroscience 1984; 12:951–958.PubMedGoogle Scholar
  109. 109.
    Lozada A, Maegele M, Stark H et al. Traumatic brain injury results in mast cell increase and changes in regulation of central histamine receptors. Neuropathol Appl Neurobiol 2005; 31:150–162.PubMedGoogle Scholar
  110. 110.
    Mohanty S et al. Role of histamine in traumatic brain edema. An experimental study in the rat. J Neurol Sci 1989; 90:87–97.PubMedGoogle Scholar
  111. 111.
    WaskiewiczJ, Molchanova L, Walajtys-Rode E et al. Hypoxia and ischemia modifies histamine metabolism and transport in brain synaptosomes. Resuscitation 1988; 16:287–293.PubMedGoogle Scholar
  112. 112.
    Lefranc F, Yeaton P, Brotchi J et al. Cimetidine, an unexpected anti-tumor agent and its potential for the treatment of glioblastoma (review). Int J Oncol 2006; 28:1021–1030.PubMedGoogle Scholar
  113. 113.
    Adachi N, Itoh Y, Oishi R et al. Direct evidence for increased continuous histamine release in the striatum of conscious freely moving rats produced by middle cerebral artery occlusion. J Cereb Blood Flow Metab 1992; 12:477–483.PubMedGoogle Scholar
  114. 114.
    Adachi N, Oishi R, Saeki K. Changes in the metabolism of histamine and monoamines after occlusion of the middle cerebral artery in rats. J Neurochem 1991; 57:61–66.PubMedGoogle Scholar
  115. 115.
    Adachi N. Cerebral ischemia and brain histamine. Brain Res Brain Res Rev 2005; 50:275–286.PubMedGoogle Scholar
  116. 116.
    Basbaum AI, Fields HL. Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu Rev Neurosci 1984; 7:309–338.PubMedGoogle Scholar
  117. 117.
    Panula P et al. Histamine-immunoreactive nerve fibers in the mammalian spinal cord. Brain Res 1989; 484:234–239.PubMedGoogle Scholar
  118. 118.
    Panula P, Pirvola U, Auvinen S et al. Histamine-immunoreactive nerve fibers in the rat brain. Neuroscience 1989; 28:585–610.PubMedGoogle Scholar
  119. 119.
    Parolaro D et al. Histamine as a central modulator of rat intestinal transit. J Pharmacol Exp Ther 1989; 249:324–328.PubMedGoogle Scholar
  120. 120.
    Bhattacharya SK, Parmar SS. Antinociceptive effect of intracerebroventricularly administered histamine in rats. Res Commun Chem Pathol Pharmacol 1985; 49:125–136.PubMedGoogle Scholar
  121. 121.
    Thoburn KK, Hough LB, Nalwalk JW et al. Histamine-induced modulation of nociceptive responses. Pain 1994; 58:29–37.PubMedGoogle Scholar
  122. 122.
    Glick SD, Crane LA. Opiate-like and abstinence-like effects of intracerebral histamine administration in rats. Nature 1978; 273:547–549.PubMedGoogle Scholar
  123. 123.
    Malmberg-Aiello P, Lamberti C, Ghelardini C et al. Role of histamine in rodent antinociception. Br J Pharmacol 1994; 111:1269–1279.PubMedGoogle Scholar
  124. 124.
    Malmberg-Aiello P, Lamberti C, Ipponi A et al. Evidence for hypernociception induction following histamine H1 receptor activation in rodents. Life Sci 1998; 63:463–476.PubMedGoogle Scholar
  125. 125.
    Mobarakeh JI et al. Enhanced antinociception by intracerebroventricularly administered orexin A in histamine H1 or H2 receptor gene knockout mice. Pain 2005; 118:254–262.PubMedGoogle Scholar
  126. 126.
    Cannon KE, Leurs R, Hough LB. Activation of peripheral and spinal histamine H3 receptors inhibits formalin-induced inflammation and nociception, respectively. Pharmacol Biochem Behav 2007; 88:122–129.PubMedGoogle Scholar
  127. 127.
    Cannon KE et al. Activation of spinal histamine H3 receptors inhibits mechanical nociception. Eur J Pharmacol 2003; 470:139–147.PubMedGoogle Scholar
  128. 128.
    Cannon KE, Hough LB. Inhibition of chemical and low-intensity mechanical nociception by activation of histamine H3 receptors. J Pain 2005; 6:193–200.PubMedGoogle Scholar
  129. 129.
    Coruzzi G, Adami M, Guaita E et al. Anti-inflammatory and antinociceptive effects of the selective histamine H4-receptor antagonists JNJ7777120 and VUF6002 in a rat model of carrageenan-induced acute inflammation. Eur J Pharmacol 2007; 563:240–244.PubMedGoogle Scholar

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© Landes Bioscience and Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Institute of BiomedicineUniversity of HelsinkiFinland

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